Calcitonin is known as a polypeptide having useful pharmacologic activities such as potent hypocalcemic and hypophosphatemic activities, bone formation-stimulating and bone resorption-inhibiting activities, urinary phosphate excretion-promoting activity and so on. Calcitonin has been isolated, by extraction, from the thyroids of various mammalian animals inclusive of man and the ultimobranchial bodies of fish, cyclostomes and fowls and its primary amino acid sequence has been established. Based on this amino acid sequence, a number of synthetic calcitonin analogs have been synthesized and reported. All the known species of calcitonin of animal origin are polypeptides consisting of 32 amino acids each, with the 1- and 7-positions thereof being invariably L-cysteine residues whose mercapto groups are bound to each other to form a disulfide linkage and the carboxy-terminal amino acid residue being prolinamide. Because of the presence of said disulfide linkage within the molecule, these naturally-occurring calcitonins are not as stable in solution as desired.
Therefore, a process for producing a synthetic calcitonin has been developed in which L-cysteine resides in positions-1 and -7 are replaced with .alpha.-L-aminosuberic acid of the following formula: ##STR3##
In this process, a peptide of the formula (SEQ ID NO: 2); ##STR4## (wherein X means a hydroxyl group, a carboxy-protecting group which is commonly used in peptide chemistry or an amino acid residue or peptide residue which is necessary to form calcitonin, and each amino acid residue may be protected with a protective group commonly used in peptide chemistry) is subjected to cyclization in liquid phase and the necessary fragments are further coupled thereto in liquid phase (hereinafter referred to as liquid phase synthesis) to synthesize the desired calcitonin derivative [Japanese Patent Publication No. 41677/1978, Japanese Patent Laid-open No. 112099/1986, Japanese Patent Laid-open No. 203699/1988 and Farumashia Review No. 3 "Seeking New Drugs--Physiologically Active Peptides" (edited by Farumashia Review Committee), P. 153-154].
In this and other processes, however, the solubility of the peptide varies delicately as the number of constituent amino acids increases, so that it becomes increasingly difficult to find an appropriate solvent. Moreover, owing to this very fact, the difficulty of fractionation of the desired polypeptide from the unreacted starting compounds and by-products is also increased. Particularly in the cyclization reaction, formation of by-products must be suppressed to a minimum. Therefore, the conventional method for liquid-phase synthesis of calcitonin is low in yield and cannot be considered to be commercially acceptable.
It is, therefore, an object of the present invention to provide peptides or acid addition salts or complex compounds thereof, which are useful for the production of cyclic peptides, particularly elcatonin which is a calcitonin derivative.
It is another object of the invention to provide novel and commercially useful processes for producing cyclic peptides, particularly elcatonin which is a calcitonin derivative, in good yield.